The pathogenesis of orofacial herpes simplex virus (HSV) infection in young guinea pigs was investigated. It was observed that, despite relative prolonged persistence of the virus in the skin lesions, only small amounts of virus reached the trigeminal ganglion, and that a latent HSV infection was established only in about 30% of the infected guinea pigs. Guinea pigs surviving the primary HSV infection can be reinfected with the homologous virus at the site of the primary reinoculation, despite the presence of HSV-specific serum antibodies. Young guinea pigs inoculated with HSV in the orofacial area were irradiated with UV light: no skin lesions developed, but one third of the irradiated guinea pigs with latent HSV infection, were found to harbour free HSV in trigeminal ganglia homogenates after UV exposure. The ability of several antiviral compounds to prevent the establishment of latent infection in hairless mice was investigated. Phosphonoformate, adenine arabinoside and its monophosphate were ineffective, but phosphonoacetate and mainly acycloguanosine proved to be highly effective. HSV-infected hairless mice with evidence of latent infection in spinal ganglia did not develop latent infections in the trigeminal ganglia upon reinfection in the orofacial area. The in vitro reactivation of HSV in latently infected trigeminal ganglia of mice was delayed in the presence of interferon, whereas the presence of anti-interferon serum facilated the reactivation of the latent virus.